Anti-notch3 agonist antibodies and their use in the treatment of notch3-related diseases

Abstract

The present invention relates to agonist antibodies that specifically bind to Notch 3 and activate signaling. The present invention includes antibodies binding to an epitope comprising the first Lin12 domain. The present invention also includes uses of these antibodies to treat or prevent Notch 3 related diseases or disorders.

1 . A method of treating a Notch3 receptor related disease or disorder comprising administering to a mammal a monoclonal antibody that specifically binds to Notch3 receptor, wherein the antibody specifically binds to an epitope in SEQ ID NO:10, and wherein the antibody activates Notch3 receptor-mediated signaling through the Notch3 receptor independent of ligand binding to the Notch3 receptor. 
     
     
         2 . The method of  claim 1 , wherein the disease is a neurodegenerative disease. 
     
     
         3 . The method of  claim 1 , wherein the disease is CADASIL, familial hemiplegic migraine (FHM), familial paroxytic ataxia, or Alagille syndrome. 
     
     
         4 . The method of  claim 1 , wherein the Notch3 receptor related disease or disorder is associated with Notch3 receptor inactivation. 
     
     
         5 . The method of  claim 1 , wherein the mammal is a human. 
     
     
         6 . The method of  claim 1 , wherein the antibody is an antigen-binding antibody fragment. 
     
     
         7 . The method of  claim 1 , wherein the antibody is a single chain Fv. 
     
     
         8 . The method of  claim 1 , wherein the antibody is a human, humanized, or chimeric antibody. 
     
     
         9 . The method of  claim 1 , wherein the antibody comprises a variable heavy (VH) chain region comprising CDR-H1 of SEQ ID NO:4, CDR-H2 of SEQ ID NO:5, and CDR-H3 of SEQ ID NO:6, and a variable light (VL) chain region comprising CDR-L1 of SEQ ID NO:7, CDR-L2 of SEQ ID NO:8, and CDR-L3 of SEQ ID NO:9. 
     
     
         10 . The method of  claim 9 , wherein the VH chain region comprises SEQ ID NO:2, and the VL chain region comprises SEQ ID NO:3.